tbuckley/cabot-search huggingface dataset:
Small Cell Lung Cancer in Light/Never Smokers – A Role for Molecular Testing?
Authors: Gordon Taylor Moffat, Tao Wang, Andrew G. Robinson
Journal: Journal of the National Comprehensive Cancer Network (2023)

This report describes the management of small cell lung cancer (SCLC) transformation in a patient with untreated ALK-mutated advanced disease and a minimal smoking history, and a separate case of a de novo SCLC in a lifelong nonsmoker found to have a potentially targetable ERBB2 alteration. In the first case, chemotherapy followed by a targeted inhibitor was chosen due to the presence of the ALK rearrangement, as well as a somewhat discordant response to induction chemotherapy, suggesting possible progression of the ALK inhibitor-sensitive component. Molecular testing for the identification of driver mutations should be considered in patients with SCLC who have light/never smoking histories in order to help understand the incidence and ultimate optimal management strategies.
Cognitive impairments correlate with increased central nervous system immune activation after allogeneic haematopoietic stem cell transplantation
Authors: Erik Boberg, Nadir Kadri, Daniel W Hagey, Lilly Schwieler, Samir El Andaloussi, Sophie Erhardt, Ellen Iacobaeus, Katarina Le Blanc
Journal: Leukemia (2023)

Abstract Murine studies indicate that, after allogeneic haematopoietic stem cell transplantation (aHSCT), donor-derived macrophages replace damaged microglia and alloreactive T-cells invade the central nervous system (CNS). The clinical relevance of this is unknown. We assessed CNS immune surveillance and metabolic activity involved in neuronal survival, in relation to fatigue and cognitive dysfunction in 25 long-term survivors after aHSCT. Patients with cognitive dysfunction exhibited increased proportions of activated T-cells and CD16 + NK-cells in the cerebrospinal fluid (CSF). Immune cell activation was paralleled with reduced levels of anti-inflammatory factors involved in T-cell suppression (transforming growth factor-β, programmed death ligand-1), NK-cell regulation (poliovirus receptor, nectin-2), and macrophage and microglia activation (CD200, chemokine [C-X3-C motif] ligand-1). Additionally, the CSF mRNA expression pattern was associated with neuroinflammation and oxidative stress. Furthermore, proteomic, and transcriptomic studies demonstrated decreased levels of neuroprotective factors, and an upregulation of apoptosis pathway genes. The kynurenine pathway of tryptophan metabolism was activated in the CNS of all aHSCT patients, resulting in accumulation of neurotoxic and pro-inflammatory metabolites. Cognitive decline and fatigue are overlooked but frequent complications of aHSCT. This study links post-transplant CNS inflammation and neurotoxicity to our previously reported hypoactivation in the prefrontal cortex during cognitive testing, suggesting novel treatment targets.
OX40 agonism enhances PD-L1 checkpoint blockade by shifting the cytotoxic T cell differentiation spectrum
Authors: Tetje C. van der Sluis, Guillaume Beyrend, Esmé T.I. van der Gracht, Tamim Abdelaal, Simon P. Jochems, Robert A. Belderbos, Thomas H. Wesselink, Suzanne van Duikeren, Floortje J. van Haften, Anke Redeker, Laura F. Ouboter, Elham Beyranvand Nejad, Marcel Camps, Kees L.M.C. Franken, Margot M. Linssen, Peter Hohenstein, Noel F.C.C. de Miranda, Hailiang Mei, Adriaan D. Bins, John B.A.G. Haanen, Joachim G. Aerts, Ferry Ossendorp, Ramon Arens
Journal: Cell Reports Medicine (2023)

Immune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high-dimensional single-cell profiling, we interrogate whether the landscape of T cell states in the peripheral blood predict responses to combinatorial targeting of the OX40 costimulatory and PD-1 inhibitory pathways. Single-cell RNA sequencing and mass cytometry expose systemic and dynamic activation states of therapy-responsive CD4+ and CD8+ T cells in tumor-bearing mice with expression of distinct natural killer (NK) cell receptors, granzymes, and chemokines/chemokine receptors. Moreover, similar NK cell receptor-expressing CD8+ T cells are also detected in the blood of immunotherapy-responsive cancer patients. Targeting the NK cell and chemokine receptors in tumor-bearing mice shows the functional importance of these receptors for therapy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use and targeting of dynamic biomarkers on T cells to improve cancer immunotherapy.
Continuous transcriptome analysis reveals novel patterns of early gene expression in Drosophila embryos
Authors: J. Eduardo Pérez-Mojica, Lennart Enders, Joseph Walsh, Kin H. Lau, Adelheid Lempradl
Journal: Cell Genomics (2023)

The transformative events during early organismal development lay the foundation for body formation and long-term phenotype. The rapid progression of events and the limited material available present major barriers to studying these earliest stages of development. Herein, we report an operationally simple RNA sequencing approach for high-resolution, time-sensitive transcriptome analysis in early (≤3 h) Drosophila embryos. This method does not require embryo staging but relies on single-embryo RNA sequencing and transcriptome ordering along a developmental trajectory (pseudo-time). The resulting high-resolution, time-sensitive mRNA expression profiles reveal the exact onset of transcription and degradation for thousands of transcripts. Further, using sex-specific transcription signatures, embryos can be sexed directly, eliminating the need for Y chromosome genotyping and revealing patterns of sex-biased transcription from the beginning of zygotic transcription. Our data provide an unparalleled resolution of gene expression during early development and enhance the current understanding of early transcriptional processes.
David Oliver: Can NHS England’s recovery plan for urgent and acute care deliver?
Authors: David Oliver
Journal: BMJ (2023)

NHS England recently published its Delivery Plan for Recovering Urgent and Emergency Care Services ,1 with goals and actions for the next two years. Its chief executive, Amanda Pritchard, said that there would shortly be a workforce plan—a “once in a generation opportunity to put the NHS on sustainable footing.”2 Every part of urgent and acute care is struggling to cope. Ambulance response times, handover delays at emergency departments, overcrowding and long waits in departments, full hospital beds, and delayed discharges of medically stable patients requiring poorly resourced community services have all compounded the staffing problems.3 It’s good to see politicians belatedly acknowledging these challenges and NHS England (equally belatedly) setting out proposals to tackle them, under six key themes:
CD103 and CD39 coexpression identifies neoantigen-specific cytotoxic T cells in colorectal cancers with low mutation burden
Authors: Jitske van den Bulk, Manon van der Ploeg, Marieke E Ijsselsteijn, Dina Ruano, Ruud van der Breggen, Rebekka Duhen, Koen C M J Peeters, Arantza Fariña-Sarasqueta, Els M E Verdegaal, Sjoerd H van der Burg, Thomas Duhen, Noel F C C de Miranda
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Expression of CD103 and CD39 has been found to pinpoint tumor-reactive CD8 + T cells in a variety of solid cancers. We aimed to investigate whether these markers specifically identify neoantigen-specific T cells in colorectal cancers (CRCs) with low mutation burden. Experimental design Whole-exome and RNA sequencing of 11 mismatch repair-proficient (MMR-proficient) CRCs and corresponding healthy tissues were performed to determine the presence of putative neoantigens. In parallel, tumor-infiltrating lymphocytes (TILs) were cultured from the tumor fragments and, in parallel, CD8 + T cells were flow-sorted from their respective tumor digests based on single or combined expression of CD103 and CD39. Each subset was expanded and subsequently interrogated for neoantigen-directed reactivity with synthetic peptides. Neoantigen-directed reactivity was determined by flow cytometric analyses of T cell activation markers and ELISA-based detection of IFN-γ and granzyme B release. Additionally, imaging mass cytometry was applied to investigate the localization of CD103 + CD39 + cytotoxic T cells in tumors. Results Neoantigen-directed reactivity was only encountered in bulk TIL populations and CD103 + CD39 + (double positive, DP) CD8 + T cell subsets but never in double-negative or single-positive subsets. Neoantigen-reactivity detected in bulk TIL but not in DP CD8 + T cells could be attributed to CD4 + T cells. CD8 + T cells that were located in direct contact with cancer cells in tumor tissues were enriched for CD103 and CD39 expression. Conclusion Coexpression of CD103 and CD39 is characteristic of neoantigen-specific CD8 + T cells in MMR-proficient CRCs with low mutation burden. The exploitation of these subsets in the context of adoptive T cell transfer or engineered T cell receptor therapies is a promising avenue to extend the benefits of immunotherapy to an increasing number of CRC patients.
Changes in circulating tumor DNA and outcomes in solid tumors treated with immune checkpoint inhibitors: a systematic review
Authors: Laith Al-Showbaki, Brooke Wilson, Faris Tamimi, Consolacion Molto, Abhenil Mittal, David W Cescon, Eitan Amir
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Quantification of circulating tumor DNA (ctDNA) levels is a reliable prognostic tool in several malignancies. Dynamic changes in ctDNA levels in response to treatment may also provide prognostic information. Here, we explore the value of changes in ctDNA levels in response to immune checkpoint inhibitors (ICIs). Methods We searched MEDLINE (host: PubMed) for trials of ICIs in advanced solid tumors in which outcomes were reported based on change in ctDNA levels. ctDNA reduction was defined as reported in individual trials. Typically, this was either &gt;50% reduction or a reduction to undetectable levels. We extracted HRs and related 95% CIs and/or p values comparing ctDNA reduction versus no reduction for progression-free survival (PFS) and/or overall survival (OS). Data were then pooled in a meta-analysis. Variation in effect size was examined using subgroup analyses. Results Eighteen trials were included in the meta-analysis. ctDNA levels were detectable in all participants in all studies prior to initiation of ICIs. A reduction in ctDNA measured 6–16 weeks after starting treatment was associated with significantly better PFS (HR 0.20; 95% CI, 0.14 to 0.28; p&lt;0.001). Similarly, OS was superior in patients with reduced ctDNA levels (HR 0.18; 95% CI, 0.12 to 0.26; p&lt;0.001). The results were consistent across all disease sites, lines of treatment, magnitude of change (to undetectable vs &gt;50% reduction) and whether treatment exposure comprised single or combination ICIs. Conclusions In advanced solid tumors, a reduction in ctDNA levels in response to ICIs is associated with substantial improvements in outcome. ctDNA change is an early response biomarker which may allow for de-escalation of cross-sectional imaging in patients receiving ICIs or support treatment de-escalation strategies.
National and regional prevalence of SARS-CoV-2 antibodies in primary and secondary school children in England: the School Infection Survey, a national open cohort study, November 2021SARS-CoV-2 antibody prevalence in school children
Authors: Annabel A Powell, Georgina Ireland, Rebecca Leeson, Andrea Lacey, Ben Ford, John Poh, Samreen Ijaz, Justin Shute, Peter Cherepanov, Richard Tedder, Christian Bottomley, Fiona Dawe, Punam Mangtani, Peter Jones, Patrick Nguipdop-Djomo, Shamez N Ladhani
Journal: Journal of Infection (2023)

SARS-CoV-2 infection rates are likely to be underestimated in children because of asymptomatic or mild infections. We aim to estimate national and regional prevalence of SARS-CoV-2 antibodies in primary (4-11 years old) and secondary (11-18 years old) school children between 10 November and 10 December 2021.Cross-sectional surveillance in England using two-stage sampling, firstly stratifying into regions and selecting local authorities, then selecting schools according to a stratified sample within selected local authorities. Participants were sampled using a novel oral fluid-validated assay for SARS-CoV-2 spike and nucleocapsid IgG antibodies.4980 students from 117 state-funded schools (2706 from 83 primary schools, 2274 from 34 secondary schools) provided a valid sample. After weighting for age, sex, and ethnicity, and adjusting for assay accuracy, the national prevalence of SARS-CoV-2 antibodies in primary school students, who were all unvaccinated, was 40.1% (95% CI 37.3-43.0). Antibody prevalence increased with age (p < 0.001) and was higher in urban than rural schools (p = 0.01). In secondary school students, the adjusted, weighted national prevalence of SARS-CoV-2 antibodies was 82.4% (95% CI 79.5-85.1); including 71.5% (95% CI 65.7-76.8) in unvaccinated and 97.5% (95% CI 96.1-98.5) in vaccinated students. Antibody prevalence increased with age (p < 0.001), and was not significantly different in urban versus rural students (p = 0.1).In November 2021, using a validated oral fluid assay, national SARS-CoV-2 seroprevalence was estimated to be 40.1% in primary school students and 82.4% in secondary school students. In unvaccinated children, this was approximately threefold higher than confirmed infections highlighting the importance of seroprevalence studies to estimate prior exposure.Deidentified study data are available for access by accredited researchers in the ONS Secure Research Service (SRS) for accredited research purposes under part 5, chapter 5 of the Digital Economy Act 2017. For further information about accreditation, contact Research.support@ons.gov.uk or visit the SRS website.
Senescent cancer cell vaccines induce cytotoxic T cell responses targeting primary tumors and disseminated tumor cells
Authors: Yue Liu, Joanna Pagacz, Donald J Wolfgeher, Kenneth D Bromerg, Jacob V Gorman, Stephen J Kron
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immune tolerance contributes to resistance to conventional cancer therapies such as radiation. Radiotherapy induces immunogenic cell death, releasing a burst of tumor antigens, but this appears insufficient to stimulate an effective antitumor immune response. Radiation also increases infiltration of cytotoxic T lymphocytes (CTLs), but their effector function is short lived. Although CTL exhaustion may be at fault, combining immune checkpoint blockade with radiation is insufficient to restore CTL function in most patients. An alternative model is that antigen presentation is the limiting factor, suggesting a defect in dendritic cell (DC) function.Building on our prior work showing that cancer cells treated with radiation in the presence of the poly(ADP-ribose) polymerase-1 inhibitor veliparib undergo immunogenic senescence, we reexamined senescent cells (SnCs) as preventative or therapeutic cancer vaccines. SnCs formed in vitro were cocultured with splenocytes and evaluated by scRNA-seq to examine immunogenicity. Immature bone-marrow-derived DCs cocultured with SnCs were examined for maturation and activation by flow cytometry and T cell proliferation assays. Viable SnCs or SnC-activated DCs were injected subcutaneously, and vaccine effects were evaluated by analysis of immune response, prevention of tumor engraftment, regression of established tumors and/or potentiation of immunotherapy or radiotherapy.Murine CT26 colon carcinoma or 4T1 mammary carcinoma cells treated with radiation and veliparib form SnCs that promote DC maturation and activation in vitro, leading to efficient, STING-dependent CTL priming. Injecting mice with SnCs induces antigen-specific CTLs and confers protection from tumor engraftment. Injecting immunogenic SnCs into tumor-bearing mice increases inflammation with activated CTLs, suppresses tumor growth, potentiates checkpoint blockade, enhances radiotherapy and blocks colonization by disseminated tumor cells. Addressing the concern that reinjecting tumor cells into patients may be impractical, DCs activated with SnCs in vitro were similarly effective to SnCs in suppressing established tumors and blocking metastases.Therapeutic vaccines based on senescent tumor cells and/or SnC-activated DCs have the potential to improve genotoxic and immune therapies and limit recurrence or metastasis.
Ultrasonic-controlled “explosive” hydrogels to precisely regulate spatiotemporal osteoimmune disturbance
Authors: Xiaoyu Han, Jieliang Shen, Shuyu Chen, Zhengwei Cai, Ying Zhu, Weiwei Yi, Kai Li, Weiye Cai, Bailong Tao, Wenguo Cui, Dingqun Bai
Journal: Biomaterials (2023)
Practical management of ocular surface disease in patients with atopic dermatitis, with a focus on conjunctivitis: A review
Authors: Vivian Y. Shi, Winston Chamberlain, Elaine Siegfried, Cheryl Kraff-Cooper, Kenneth Beckman, Peter Lio, Amy S. Paller, Eric Simpson
Journal: Journal of the American Academy of Dermatology (2023)

Atopic dermatitis (AD) is a chronic inflammatory skin disease that can significantly decrease quality of life. AD is commonly associated with comorbidities including ocular surface disease (OSD). Conjunctivitis is the most common OSD associated with AD and can increase in incidence with use of monoclonal antibody biologics that target the type 2 inflammatory pathway. The objective of this review is to raise awareness of comorbid OSD in AD patients that dermatologists may encounter, with a focus on conjunctivitis, and equip dermatologists to address mild ocular concerns. We provide background on the subtypes and pathogenesis of comorbid OSD in AD patients and describe OSD associated with type 2 inflammation-inhibiting AD biologics. We also discuss screening and diagnosis, recommended treatment options for dermatologists, and when to refer to an eye care specialist. This multispecialty approach aims to support the overall health of AD patients and provide optimal patient care.
Comparative analysis of CRISPR off-target discovery tools following ex vivo editing of CD34+ hematopoietic stem and progenitor cells
Authors: M. Kyle Cromer, Kiran R. Majeti, Garrett R. Rettig, Karthik Murugan, Gavin L. Kurgan, Nicole M. Bode, Jessica P. Hampton, Christopher A. Vakulskas, Mark A. Behlke, Matthew H. Porteus
Journal: Molecular Therapy (2023)

While a number of methods exist to investigate CRISPR offtarget (OT) editing, few have been compared head-to-head in primary cells after clinically relevant editing processes.Therefore, we compared in silico tools (COSMID, CCTop, and Cas-OFFinder) and empirical methods (CHANGE-Seq, CIRCLE-Seq, DISCOVER-Seq, GUIDE-Seq, and SITE-Seq) after ex vivo hematopoietic stem and progenitor cell (HSPC) editing.We performed editing using 11 different gRNAs complexed with Cas9 protein (high-fidelity [HiFi] or wild-type versions), then performed targeted next-generation sequencing of nominated OT sites identified by in silico and empirical methods.We identified an average of less than one OT site per guide RNA (gRNA) and all OT sites generated using HiFi Cas9 and a 20-nt gRNA were identified by all OT detection methods with the exception of SITEseq.This resulted in high sensitivity for the majority of OT nomination tools and COSMID, DISCOVER-Seq, and GUIDE-Seq attained the highest positive predictive value (PPV).We found that empirical methods did not identify OT sites that were not also identified by bioinformatic methods.This study supports that refined bioinformatic algorithms could be developed that maintain both high sensitivity and PPV, thereby enabling more efficient identification of potential OT sites without compromising a thorough examination for any given gRNA.
A luciferase reporter mouse model to optimize in vivo gene editing validated by lipid nanoparticle delivery of adenine base editors
Authors: Si-Yue Yu, Tiffany Carlaw, Tyler Thomson, Alexandra Birkenshaw, Genc Basha, Daniel Kurek, Cassie Huang, Jayesh Kulkarni, Lin-Hua Zhang, Colin J D Ross
Journal: Molecular Therapy (2023)

The rapid development of CRISPR genome editing technology has provided the potential to treat genetic diseases effectively and precisely. However, efficient and safe delivery of genome editors to affected tissues remains a challenge. Here, we developed luminescent ABE (LumA), a luciferase reporter mouse model containing the R387X mutation (c.A1159T) in the luciferase gene located in the Rosa26 locus of the mouse genome. This mutation eliminates luciferase activity but can be restored upon A-to-G correction by SpCas9 adenine base editors (ABEs). The LumA mouse model was validated through intravenous injection of two FDA-approved lipid nanoparticle (LNP) formulations consisting of either MC3 or ALC-0315 ionizable cationic lipids, encapsulated with ABE mRNA and LucR387X-specific guide RNA (gRNA). Whole-body bioluminescence live imaging showed consistent restoration of luminescence lasting up to 4 months in treated mice. Compared with mice carrying the wild-type luciferase gene, the ALC-0315 and MC3 LNP groups showed 83.5% ± 17.5% and 8.4% ± 4.3% restoration of luciferase activity in the liver, respectively, as measured by tissue luciferase assays. These results demonstrated successful development of a luciferase reporter mouse model that can be used to evaluate the efficacy and safety of different genome editors, LNP formulations, and tissue-specific delivery systems for optimizing genome editing therapeutics.
The blood proteomic signature of prurigo nodularis reveals distinct inflammatory and neuropathic endotypes: A cluster analysis
Authors: Varsha Parthasarathy, Karen Cravero, Lillian Xu, Junwen Deng, Zhe Sun, Sarah M. Engle, Jonathan T. Sims, Angela J. Okragly, Shawn G. Kwatra
Journal: Journal of the American Academy of Dermatology (2023)
Paroxetine is an effective treatment for refractory erythema of rosacea: Primary results from the Prospective Rosacea Refractory Erythema Randomized Clinical Trial
Authors: Ben Wang, Yingxue Huang, Yan Tang, Zhixiang Zhao, Wei Shi, Dan Jian, Fangfen Liu, Qiong Gao, Peiru Wang, Jie Yang, Lin Li, Hongfu Xie, Ji Li
Journal: Journal of the American Academy of Dermatology (2023)